1-substituted cycloheptimidazol-2(1h)-one compounds



United States Patent 3,293,260 l-SUBSTITUTED CYCLOHEPTINIIDAZOL-2(1H)- ONE COMPOUNDS Genshun Sunagawa, Hideo Nakao, Junichi Nakazawa,

Nobuo Sonia, Yasunobu Sato, Mitsuo Watatani, Yasuhiro Matsumoto, and Shinsaku Kobayashi, all of Shinagawa-ku, Tokyo, Japan, assignors to Sankyo Company, Limited, Tokyo, Japan N Drawing. Filed Sept. 10, 1963, Ser. No. 307,808

Claims priority, application Japan, Sept. 17, 1962, 37/40,284; Aug. 16, 1963, 38/ 42,967 9 Claims. (Cl. 260309.6)

This invention relates to new chemical compounds. More particularly, it is concerned with new l-substituted cycloheptimidazol-2(1H-) -one compounds having the general formula N KPH 0 N I wherein X is hydrogen, a lower alkyl group, which may be either straight or branched in the chain structure and contains from 1 to carbon atoms such as methyl, ethyl, propyl, isopropyl, isobutyl or isoamyl, an unsubstituted or substituted phenyl group such as phenyl, p-nitrophenyl, p-chlorophenyl or p-methoxyphenyl, an aralkyl group such as benzyl or phenethyl having or not having one or more substituents on the phenyl moiety, halogen, nitro group, hydroxy group, an alkoxy group containing from 1 to 5 carbon atoms such as methoxy or ethoxy, an aliphatic or aromatic acyl group such as formyl, acetyl, propionyl or benzoyl having or not having one or more substituents on the phenyl moiety, an alkoxycarbonyl group containing from 2 to 6 carbon atoms such as methoxycarbonyl or ethoxycarbonyl or an unsubstituted or substituted amino group such as amino, mono-loweralkylamino, di-loweralkyl-amino or acylamino, Xs may be same or different one another when n is 2 or 3, n is an integer from 1 to 3 and Y is an unsubstituted or substituted aminoalkyl group having from 1 to 5 carbon atoms on the alkyl moiety such as dimethylaminomethyl, l-dimethylaminoethyl Z-dimethylaminoethyl, l-methyl-Z- dimethylaminoethyl or 3-dimethylaminopropyl, piperidinoalkyl group having from 1 to 5 carbon atoms on the alkyl moiety such as piperidinomethyl or 3-piperidinopropyl, morpholinoalkyl group having from 1 to 5 carbon atoms on the alkyl moiety such as morpholinomethyl, 2- morpholinoethyl or 3-morpholinopropyl, pyrrolidinoalkyl group having from 1 to 5 carbon atoms on the alkyl moiety such as pyrrolidinomethyl, 2-pyrrolidinoethyl or 3-pyrrolidinopropyl, piperazinoalkyl group having from 1 to 5 carbon atoms on the alkyl moiety and having or not having one or more substituents on the piperazine moiety such as Z-piperazinoethyl, 3-piperazinopropyl or pyridylalkyl group having from 1 to 5 carbon atoms on the alkyl moiety and having or not having one or more substituents on the pyridine moiety such as Z-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl an unsaturated lower aliphatic hydrocarbon radical containing from 2 to 5 carbon atoms such as vinyl (CH=CH allyl (CH CH=CH propargyl (CH2CECH), Z-butenyl Z-pentenyl (CH CH=CHCH CH or 3-butynyl (CH CH CECH), alkoxyalkyl group having from 1 to 5 carbon atoms on the alkyl moiety and having from 1 to 5 carbon atoms on the alkoxy moiety such as methoxymethyl, ethoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl or ethoxybutyl or benzyloxy- Patented Dec. 20, 1966 alkyl group having 1 to 5 carbon atoms on the alkyl moiety such as benzyloxymethyl or benzyloxyethyl. It also relates to the process for preparing such compounds.

The l-substituted cycloheptimidazol-2(1H)-one compounds having the above-described Formula I are novel compounds unknown in the prior art and possess potent analgesic and anti-inflammatory activities.

It is an object of the present invention to provide novel l-substituted cycloheptimidazol-Z 1H -one compounds having the above-described Formula I useful as analgesic and anti-inflammatory agent. Another object is the provision of a process for the preparation of said compounds. Other objects will become apparent from the following description.

According to the present invention, the l-substituted cyc1oheptimidazol-2(lH)-one compounds of the abovedescribed Formula I may be prepared by reacting cycloheptimidazolone compounds having the general formula %N X, 0 V a) wherein X and n have the same meanings as described above or alkali metal salts thereof with compounds having the general formula YZ (III) wherein Y has the same meanings as described above and Z is halogen atom or an active ester group such as tosyl group.

In carrying out the process according to the present invention, the reaction is preferably carried out in water, a suitable inert organic solvent such as alcohol, dioxane, benzene or toluene, or a suitable inert aqueous organic solvent such as aqueous alcohol or aqueous dioxane. The temperature at which the reaction is carried out is preferably reflux temperature, but this may be raised or lowered, if desired. In cases where it is desired to use cycloheptimidazolone compounds of the above-described Formula II in the free form as the reactant, the cycloheptimidazolone compounds can be reacted with compounds of the above-described Formula III in the presence of a condensing agent to produce the desired compounds having the above-described Formula I. Examples of such condensing agent include alkali metals such as sodium, potassium and lithium, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal amides such as sodium amide and potassium amide, alkali metal-hydrocarbon compounds such as butyl lithium, phenyl lithium and phenyl potassium, alkali metal alcoholates such as potassium butoxide and sodium ethoxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate and the like. In cases where it is desired to use cycloheptimidazolone compounds of the above-described Formula II in the salt form as the reactant, the cycloheptimidazolone compounds in the salt form can be reacted with compounds of the above-described Formula III in the absence of a condensing agent to obtain the desired products. In the latter cases, if desired, the reaction may also be effected by alkali metal salts of cycloheptimidazolone compounds of the abovedescribed Formula II and compounds of the above-described Formula III at a temperature of about C. to about C. in the absence of a condensing agent and solvent.

After completion of the reaction, the reaction product may be isolated from the reaction mixture by one of the convention methods. For example, when organic solvent such as ethanol is used as the reaction solvent, the reaction mixture is concentrated, the residue is extracted with benzene or chloroform, the extract is distilled and the crude crystalline residue thus obtained is recrystallized from a suitable organic solvent such as ethanol. When water is used as the reaction solvent, the reaction mixture, after completion of the reaction, is directly extracted with benzene or chloroform and the extract is treated in a manner similar to that described above.

The following examples are given for the purpose of illustrating the present invention, but are not intended to be limiting on the scope thereof.

Example 1 A mixture of 4 g. of sodium salt of cycloheptimidazol- 2(1H)-one and 2.8 g. of Z-dimethylaminoethyl chloride in 50 ml. of ethanol is heated under reflux for 6 hours. After cooling the reaction mixture, the insoluble inorganic substance which precipitates is filtered off and the filtrate is concentrated under reduced pressure. Water is added to the concentrate, the mixture is made alkaline and the resulting mixture is extracted with chloroform. The chloroform is distilled off from the chloroform extract and the residue thus obtained is recrystallized from benzene to give 3 g. of 1-(2-dimethylamin0ethyl) cycloheptimidazol-2(1H)-one melting at 134 C.

Analysis.Calculated for C H ON r C, 66.34; H, 6.96; N, 19.34. Found: C, 66.65; H, 6.84; N, 19.03.

Example 2 C15H21ON3Z N, 16.21.

Example 3 To a solution of 76 mg. of metallic sodium in 10 ml. of ethanol are added 573 mg. of -nitrocycloheptimidazol-2(1H)-one and 322 mg. of 2-dimethylaminoethyl chloride and the mixture is heated under reflux with stirring. After completion of the reaction, the solvent is distilled off and the residue is recrystallized from methanol to give 200 mg. of 1-(2-dimethylaminoethyl)-6-nitrocycloheptimidazol-2(1H)-one having decomposition point of 210 C.

Analysis-Calculated for C H O N C, 54.95; H, 5.38; N, 21.37. Found: C, 54.65; H, 5.09; N, 21.15.

Example 4 To a solution of 51 mg. of metallic sodium dissolved in 10 ml. of ethanol are added 400 mg. of 6-chlorocycloheptimidazol-2(1H)-one and 268 mg. of 3-dimethylaminopropyl chloride and the mixture is heated under reflux with stirring. After cooling, the reaction mixture is filtered, the filtrate is distilled under reduced pressure, the residue is dissolved in ethyl acetate and the solution thus obtained is passed through an alumina column. The solvent is distilled off from the efliuent and the residue is recrystallized from ethyl acetate to give 180 mg. of 1- (3 dimethylaminopropyl) 6 chlorocycloheptimidazol- 2(1H)-one melting at 168 to 169 C.

Annlysis.Calculated for C13HGON3CII C, 58.75; H, 6.07; N, 15.81. Found: C, 58.43; H, 6.00; N, 16.05.

Example To a solution of 1.5 g. of cycloheptimidazol-2(1H)- one dissolved on ml. of 5% sodium hydroxide solution is added a solution of 1.3 g. of 2-chloromethylpyri- Example 6 To a solution of 70 mg. of metallic sodium dissolved in 10 ml. of ethanol is added 500 mg. of 3-chloromethylpyridine hydrochloride. After a short period of time, 500 mg. of sodium salt of cycloheptimidazol-2(1H)-one is added to the mixture and the mixture is heated under reflux for 5 hours. After cooling, the insoluble substance is filtered off, the filtrate is concentrated and the residue is dissolved in chloroform. The chloroform solu tion is passed through an alumina column. The first colored efiiuent fractions are discarded and the remaining effluent fractions are concentrated. The residue is recrystallized from a mixture of chloroform and benzene to give 1-(3-pyridylmethyl) cycloheptimidazol-2(1H)-one melting at 173 C.

Analysis.Calculated for C H ON C, 70.87; H, 4.67; N, 17.71. Found: C, 71.02; H, 4.61; N, 17.56.

Example 7 To a solution of 420 mg. of metallic sodium dissolved in 50 mg. of ethanol are added 3.0 g. of 4-chloromethylpyridine hydrochloride and 3.0 g. of sodium salt of cycloheptimidazol-2(1H)-one and the mixture is heated under reflux for 4 hours. After cooling, the insoluble substance is filtered off, the filtrate is concentrated, the crystalline residue is dissolved in chloroform and the chloroform solution is passed through an alumina column. The first colored efiluent fractions are discarded and the remaining efliuent fractions are concentrated. The residue is recrystallized from ethanol to give 1.4 g. of 1-(4-pyridylmethyl) cycloheptimidazol-2(1H)-one melting at 204 C.

Analysis.Calculated for C14H11ON3Z C, 70.87; H, 4.67; N, 17.71. Found: C, 70.62; H, 4.59; N, 17.82.

Example 8 The solution of 2.9 g. of cycloheptimidazol-2(lH)-one dissolved in 18 ml. of 5% sodium hydroxide solution are added 3.3 g. of 3-mor-pholinopropyl chloride and 30 ml. of methanol and the mixture is heated under reflux with stirring for 3 hours. The solvent is distilled off from the reaction mixture, the residue is dissolved in water, the solution obtained is made alkaline and extracted with chloroform. The chloroform solution is extracted with 10% hydrochloric acid solution and the hydrochloric acid layer is evaporated under reduced pressure to dryness. The residue is recrystallized from ethanol to give 1-(3- morpholinopropyl) cycloheptimidazol-2( 1 H) -one dihydrochloride as pale yellow needles melting at 220 C. with decomposition.

Analysis-Calculated for C H O N 2HC1: C, 51.98; H, 6.12; N, 12.06. Found: C, 52.02; H, 6.11; N, 12.14.

Example 9 To a solution of 2.9 g. of cycloheptimidazol-2(1H)-one dissolved in 18 ml. of 5% sodium hydroxide solution are added 3.3 g. of 3-piperidinopropyl chloride and 30 ml. of ethanol and the mixture of heated under reflux with stir ring for 3 hours. After completion of the reaction, the solvent is distilled off from the reaction mixture, the residue is dissolved in chloroform and the chloroform solution is passed through an alumina column. The chloroform is distilled off from the effluent, a solution of maleic acid dissolved in ethanol is added to the oily residue and the mixture is made into a solution by heating and then cooled. The crystalline material which precipitates is Example To a suspension of 2 g. of sodium salt of cycloheptimidazol-2(lH)-one in 30 ml. of ethanol is added 1.7 g. of 2-chloro-1-dimethylaminopropane and the mixture is heated under reflux for 3 hours. After cooling, sodium chloride which precipitates is filtered off and the filtrate is concentrated under reduced presure. The residue is dissolved in chloroform and the chloroform solution is passed through an alumina column. The effluent is concentrated and the crystalline material obtained is recrystallized from benzene to give 1-(1-rnethyl-2-dimethylaminoethyl) cycloheptimidazol-2(1H)-one melting at 125 C.

Analysis.-Calculated for C H ON C, 67.50; H, 7.41. Found: C, 67.05; H, 7.38.

Example 11 A mixture of 1 g. of sodium salt of cycloheptimidazol -2(1H)-one and 1 g. of 3-dimethylaminopropyl chloride in 25 ml. of methanol is heated under reflux with stirring for 3 hours. After completion of the reaction, the reaction mixture is cooled and concentrated under reduced pressure and the residue is extracted with chloroform. The chloroform extract is concentrated, the residue is dissolved in chloroform, the chloroform solution is passed through an alumina column and the effluent is concentrated. Eethanolic hydrogen chloride solution is added to the residue, the crystalline material which precipitates is recovered by filtration and recrystallized from ethanol to give 0.7 g. of 1-(3-dimethylaminopropyl) cycloheptimidazol-2(1H)-one hydrochloride as White crystalline material melting at 261 C.

AnaIysis.-Calculated for C N N OCl :C, 51.32; H, 6.29; N, 13.81. Found: C, 51.65; H, 6.65; N, 14.01.

Example 12 A mixture of 3 g. of sodium salt of cycloheptimidazol -2(1H)-one, 2.6 g. of 2-pyrrolidinoethyl chloride and 30 ml. of ethanol is heated under reflux with stirring for 3 hours. After completion of the reaction, the reaction mixture is cooled, the insoluble substance is filtered off and the filtrate is evaporated to dryness. The crystalline material thus obtained is recrystallized from a mixture of benzene and cyclohexane to give 2.1 g. of 1-(2-pyrrolidinoethyl) cycloheptimidazol-2(1H)-one melting at 130 C.

Analysis.-Calculated for C H N O: C, 69.11; H. 7.04; N, 17.27. Found: C, 69.01; H, 7.14; N, 17.14.

Example 13 A mixture of 3 g. of sodium salt of cycloheptimidazol -2(1H)-one, 3.3 g. of 3-pyrrolidinopropyl chloride and 30 ml. of ethanol is heated under reflux with stirring for 3 hours. After completion of the reaction, the reaction mixture is cooled, the inorganic substance is filtered off, the filtrate is concentrated under reduced pressure, the residue is dissolved in chloroform and the chloroform solution is passed through an alumina column. The efliuent is evaporated to dryness and the crystalline residue is recrystallized from a mixture of benzene and cyclohexane to give 2.8 g. of 1-(3-pyrrolidinopropyl) cycloheptimidazol-2(1H)-one melting at 103 C.

Analysis.Calculated for C H N O: C, 70.00; H, 7.44; N, 16.33. Found: C, 69.96; H, 7.45; N, 16.42.

Example 14 A mixture of 1.68 g. of sodium salt of cycloheptimidazol-2(1H)-one, 2.99 g. of Z-morpholinoethyl tosylate and 20 ml. of methanol is heated under reflux with stirring for 3 hours. After completion of the reaction, the insoluble substance is filtered off, the filtrate is evaporated under reduced pressure to dryness and the residue is extracted with benzene with heating. The benzene extract is concentrated, the crystalline material which precipitates is recovered by filtration and recrystallized from benzene to give 0.8 g. of 1-(2-morpholinoethyl) cycloheptimidazol- 2(1H)-one melting at 144 C.

Analysis.Calculated for C H N O C, 64.84; H, 6.61; N, 16.21. Found: C, 64.78; H, 6.59; N, 16.19.

Example 15 A mixture of 5.5 g. of potassium salt of cycloheptimidazol-2(1H)-one and 3.4 g. of Z-dimethylaminoethyl chloride is heated at a temperature of to C. on an oil bath for 15 minutes. After cooling, benzene is added to the reaction mixture and the mixture is filtered with Warming. The filtrate is concentrated under reduced pressure and .the residue is recrystallized from benzene to give 3.2 g. of 1-(Z-dimethylaminoethyl) cycloheptimidazol-2(1H)-one as pale yellow crystalline substance melting at 134 C.

Analysis.-Calculated for C H N O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.33; H, 7.00; N, 19.35.

Example 16 A mixture of 1 g. of sodium salt of cycloheptimidazol- 2(1H)-one and 0.9 g. of propargyl bromide in 15 ml. of methanol is heated under reflux with stirring for 2 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, the residue is washed with water and recrystallized from ethanol to give 0.5 g. of 1-propargylcycloheptimidazol-2(1H)-one as pale yelloW prisms melting at 166 C.

Analysis.Calculated for C H ON C, 71.72; H, 4.38; N, 15.21. Found: C, 71.63; H, 4.56; N, 15.03.

Example 17 A mixture of 1 g. of sodium salt of cycloheptimidazol- 2(1H)-one and 1.1 g. of benzyloxymethyl chloride in 20 ml. of benzene is heated under reflux with stirring for 2.5 hours. After completion of the reaction, the reaction mixture is cooled, the insoluble substance is filtered off and the filtrate is concentrated. The crystalline material which precipitates is collected by filtration and recrystallized from benzene to give 0.7 g. of l-benzyloxymethylcycloheptimidazol-2(1H)-one melting at 114 C.

Analysis-Calculated for C H N O C, 72.16; H, 5.30; N, 10.52. Found: C, 72.14; H, 5.26; N, 10.49.

Example 18 A mixture of 1 g. of sodium salt of cycloheptimidazol- 2(1H)-one and 0.9 g. of allyl. bromide in 15 ml. of ethanol is heated under reflux with stirring for 3 hours. After completion of the reaction, the reaction mixture is concentrated under reduced pressure, the residue is extracted with chloroform and the chloroform solution is washed With water, concentrated and the-n the concentrate is passed through an alumina column. The eflluent is concentrated, ethanolic hydrogen chloride solution is added to the concentrate, the hydrochloride which precipitates is collected by filtration. The hydrochloride thus obtained is recrystallized from ethanol to give 0.3 g. of 1-allylcycloheptimidazole-2(1H)-one hydrochloride as white crystalline material melting at 212 C.

Analysis-Calculated for C H ON Cl: C, 59.33; H, 4.98; N, 12.58. Found: C, 58.89; H, 4.91; N, 12.63.

Example 19 To a suspension of 1.68 g. of sodium salt of cycloheptimidazol-2(1H)-one in 20 ml. of benzene is added 1 g. of ethoxymethylchloride and the resulting mixture is heated under reflux for 2.5 hours. After cooling, the insoluble substance is filtered off and the filtrate is concentrated under reduced pressure. The crystalline material which precipitates is collected by filtration and recrystallized from a small amount of benzene to give 1.2 g. of

7 l-ethoxymethylcycloheptimidazol 2(1H) one melting at 106 C.

Analysis.-Calculated for C H O N C, 64.69; H, 5.92; N, 13.72. Found: C, 64.55; H, 5.85; N, 13.80.

Example 20 To a suspension of 1.68 g. of sodium salt of cycloheptimidazol-2(1H)-one in 20 ml. of benzene is added dropwise 0.8 g. of meth-oxymethylchloride at a temperature below 20 C., and the resulting mixture is heated under reflux for 2 hours. After the completion of the reaction, the insoluble substance is filtered off, the filtrate is concentrated under reduced pressure. The crystalline material which precipitates is collected by filtration and recrystallized from benzene to give 0.6 g. of l-methoxymethylcycloheptimidazol-Z(1H)-one as pale yellow needles melting at 152 C.

Analysis.-Calculated for C H N O z C, 63.15; H, 5.30; N, 14.73. Found: C, 63.04; H, 5.35; N, 14.84.

Example 21 A mixture of 1.68 g. of sodium salt of cycloheptimidazol-2(lH)-one and 1.2 g. of vinyl bromide in 20 ml.

of ethanol is heated under reflux with stirring for 2 hours. After completion of the reaction, the reaction mixture is concentrated to dryness and the residue is extracted with heating with benzene. The benzene extract is concentrated under reduced pressure, the crystalline material which precipitates is collected by filtration and recrystallized from benzene to give 0.9 g. of l-vinylcycloheptimidazol-2(1H)-one as pale yellow needles melting at 168 C.

Analysis.-Calculated for C H N O: C, 69.75; H, 4.68; N, 16.27. Found: C, 69.74; H, 4.62; N, 16.37.

Example 22 Example 23 A mixture of 1 g. of sodium salt of cycloheptimidazol- A 2(1H)-one and 1.5 g. of propargyl alcohol tosyl ester in 15 ml. of ethanol is heated under reflux with stirring for 5 hours. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. The chloroform extract is extracted with hydrochloric acid, the hydrochloric acid extract is neutralized with 10% sodium hydroxide and the resulting solution is extracted with chloroform. The chloroform extract is concentrated and the residue thus obtained is recrystallized from ethanol to give 0.3 g. of 1-propargylcycloheptimidazol-2(1H)- one as pale yellow crystalline material melting at 166 C.

Example 24 To a solution of 1 g. of cycloheptimidazol-2(1H)-one in 6 ml. of 5% sodium hydroxide are added 6 ml. of

ethanol and 0.9 g. of propargyl bromide and the resulting mixture is heated under reflux on a water bath for 3 hours. After cooling, the reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. The chloroform extract is reextracted with 10% hydrochloric acid. The hydrochloric acid extract is neutralized With 10% sodium hydroxide, followed by extraction with chloroform. The chloroform extract is concentrated and the residue thus obtained is recrystallized from ethanol to give 0.4 g. of l-propargylcycloheptirnidazol-2( 1H)-one as pale yellow crystals melting at 166 C.

We claim:

1. A compound having the formula wherein X is hydrogen, a straight or branched alkyl group of 1 to 5 carbon atoms, halogen or nitro group, and Y is group, a piperidino alkyl group of 1 to 5 carbon atoms in the alkyl moiety, 8. pyrrolidino alkyl group of 1 to 5 carbon atoms in the alkyl moiety, a piperazino alkyl group of 1 to 5 carbon atoms in the alkyl moiety, a pyridylalkyl group of l to 5 carbon atoms in the alkyl moiety, an unsaturated aliphatic hydrocarbon radical of 2 to 5 carbon atoms, -(CH ),,(OR) group or group, R being an alkyl group of 1 to 5 carbon atoms and n being an integer of 1 to 5 inclusive.

2. 1 (2 dimethylaminoethy'l)cycloheptimidazol 2 (1H)-one.

3. 1 (2 pyrrolidinoethyl)cycloheptimidazol- 2(1H)- one.

4. 1-propargyylcycloheptimidazol-2 1H) -one.

5 1-allylcycloheptimidazol-Z 1H *one.

6. 1-vinylcycloheptimidazol-2 1H) -one.

7 1-methoxymethylcycloheptimida201-2 1H -one.

8. 1-ethoxymethylcycloheptimidazol-Z(1H)-one.

9. 1-benzyloxymethylcycloheptirnidazol-Z( 1H one.

References Cited by the Examiner UNITED STATES PATENTS 2,623,879 12/1952 Ringwald et al 260-3092 2,944,062 7/1960 Hotfmann et a1. 260-3092 2,965,648 12/1960 Wilgand et al 260-3 09.2 3,073,841 1/1963 Schindler 260-3092 FOREIGN PATENTS 624,446 1/ 1963 Belgium. 631,296 11/1961 Canada.

WALTER A. MODANCE, Primary Examiner.

N. TROUSOF, Assistant Examiner. 

1. A COMPOUND HAVING THE FORMULA 